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PECAM‐1 supports leukocyte diapedesis by tension‐dependent dephosphorylation of VE‐cadherin
Author(s) -
Arif Nida,
Zinnhardt Maren,
Nyamay’Antu Alengo,
Teber Denise,
Brückner Randy,
Schaefer Kerstin,
Li YuTung,
Trappmann Britta,
Grashoff Carsten,
Vestweber Dietmar
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106113
Subject(s) - dephosphorylation , microbiology and biotechnology , plakoglobin , cadherin , ve cadherin , adherens junction , phosphorylation , endocytosis , chemistry , biology , catenin , phosphatase , signal transduction , cell , biochemistry , wnt signaling pathway
Leukocyte extravasation is an essential step during the immune response and requires the destabilization of endothelial junctions. We have shown previously that this process depends in vivo on the dephosphorylation of VE‐cadherin‐Y731. Here, we reveal the underlying mechanism. Leukocyte‐induced stimulation of PECAM‐1 triggers dissociation of the phosphatase SHP2 which then directly targets VE‐cadherin‐Y731. The binding site of PECAM‐1 for SHP2 is needed for VE‐cadherin dephosphorylation and subsequent endocytosis. Importantly, the contribution of PECAM‐1 to leukocyte diapedesis in vitro and in vivo was strictly dependent on the presence of Y731 of VE‐cadherin. In addition to SHP2, dephosphorylation of Y731 required Ca 2+ ‐signaling, non‐muscle myosin II activation, and endothelial cell tension. Since we found that β‐catenin/plakoglobin mask VE‐cadherin‐Y731 and leukocyte docking to endothelial cells exert force on the VE‐cadherin–catenin complex, we propose that leukocytes destabilize junctions by PECAM‐1‐SHP2‐triggered dephosphorylation of VE‐cadherin‐Y731 which becomes accessible by actomyosin‐mediated mechanical force exerted on the VE‐cadherin–catenin complex.